scholarly journals A Genome-Wide Association Study of Susceptibility to Acute Lymphoblastic Leukemia in Adolescents and Young Adults

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 132-132
Author(s):  
Virginia Perez-Andreu ◽  
Kathryn G. Roberts ◽  
Xu Heng ◽  
Colton Smith ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Young Adults ◽  
Odds Ratio ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Risk Allele Frequency ◽  
Risk Variant ◽  
Genome Wide ◽  
Pediatric All

Abstract Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared to pediatric ALL. Age, as a continuous variable, is negatively correlated with prognosis, in spite of risk-adapted combination chemotherapy. To better understand the etiology of ALL in this age group, we performed the first genome-wide association study (GWAS) to comprehensively examine germline single nucleotide polymorphisms (SNPs) for their association with susceptibility to B-ALL in AYAs. In the discovery GWAS, we compared genotype frequency at 635,297 SNPs between 308 AYA ALL cases (age 16-39 years, treated on the Children’s Oncology Group [COG], the Alliance-Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, MD Anderson Cancer Center, and St. Jude Children’s Research Hospital trials) vs. 6,661 non-ALL controls. The association between genotypes at each SNP and ALL susceptibility was tested by using a logistic regression model after adjusting for genetic ancestries to control for population stratification. SNPs that reached P≤ 5×10-8 in the discovery GWAS were tested in an independent cohort of 82 AYA ALL cases from the COG protocols and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus on 10p14 signified by two SNPs within the GATA3 gene: rs3824662, P=2.8x10-10, odds ratio (OR)=1.77; rs3781093, P=3.2x10-9, OR=1.73, both of which were validated in the replication cohort (P=1.9x10-8 and P=4.3x10-5, respectively). We also examined the association signals in AYAs for susceptibility loci previously identified in pediatric ALL: ARID5B, IKZF1 and PIP4K2A variants were nominally significant in AYAs in the discovery GWAS and/or in the replication analysis, whereas CEBPE or CDKN2A/CDKN2B were not significant. These results imply both similarities and differences in genetic predisposition to ALL between children and AYAs. At the GATA3 locus, rs3824662 risk variant was over-represented in Philadelphia chromosome (Ph)-like ALL in AYAs (P=0.02), confirming our previous report of Ph-like ALL susceptibility variants in GATA3 (Nat Genet 45:1494). Importantly, even after excluding Ph-like cases, rs3824662 remained associated with the risk of developing ALL in AYAs, suggesting that the influence of the GATA3risk variant on ALL susceptibility in AYAs extends beyond the predisposition to Ph-like subtype. We next examined the relationship between GATA3 risk allele frequency and age at diagnosis in a cohort of unselected childhood and adolescent ALL cases enrolled in the COG P9900 protocols (N=1,827). Dividing patients into four consecutives age groups (<5, 5-10, 10-15 and >15 years), we observed a clear progressive increase in the risk allele frequency at rs3824662 (P=6.29×10-11) with increasing allelic odds ratio (i.e. relative risk of ALL conferred by each copy of the risk allele). This correlation between genotype and age was evident regardless of genetic ancestry, although the risk variant was more common among individuals with higher Native American ancestry. In contrast, the frequency of ALL susceptibility variant in ARID5B decreased progressively with increasing age at diagnosis (P=0.006), whereas PIP4K2A, CDKN2A/CDKN2B, IKZF1 and CEBPE variants were not related to age. Finally, we compared rs3824662 risk variant frequency by age in the COG P9900 protocols after stratifying the ALL cases into TCF3-PBX1, ETV6-RUNX1, hyperdiploid, MLL-rearranged and B-other. There was a trend that the risk allele was more frequent in cases older than 16 years compared to those below 16 in the five subtypes examined. In conclusion, we have identified inherited GATA3 genetic variants that strongly influence ALL susceptibility in adolescent and young adults, indicating potential age-related differences in ALL biology. Disclosures No relevant conflicts of interest to declare.

scholarly journals Genome-wide association analyses identify two susceptibility loci for pachychoroid disease central serous chorioretinopathy

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Yoshikatsu Hosoda ◽  
Masahiro Miyake ◽  
Rosa L. Schellevis ◽  
Camiel J. F. Boon ◽  
Carel B. Hoyng ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Central Serous Chorioretinopathy ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association ◽  
Susceptibility Loci ◽  
Association Analyses ◽  
Age Related ◽  
Genome Wide

AbstractThe recently emerged pachychoroid concept has changed the understanding of age-related macular degeneration (AMD), which is a major cause of blindness; recent studies attributed AMD in part to pachychoroid disease central serous chorioretinopathy (CSC), suggesting the importance of elucidating the CSC pathogenesis. Our large genome-wide association study followed by validation studies in three independent Japanese and European cohorts, consisting of 1546 CSC samples and 13,029 controls, identified two novel CSC susceptibility loci: TNFRSF10A-LOC389641 and near GATA5 (rs13278062, odds ratio = 1.35, P = 1.26 × 10−13; rs6061548, odds ratio = 1.63, P = 5.36 × 10−15). A T allele at TNFRSF10A-LOC389641 rs13278062, a risk allele for CSC, is known to be a risk allele for AMD. This study not only identified new susceptibility genes for CSC, but also improves the understanding of the pathogenesis of AMD.

scholarly journals Genome-Wide Association Study of Susceptibility Loci for T-Cell Acute Lymphoblastic Leukemia in Children

2019 ◽  
Vol 111 (12) ◽  
pp. 1350-1357 ◽  
Author(s):  
Maoxiang Qian ◽  
Xujie Zhao ◽  
Meenakshi Devidas ◽  
Wenjian Yang ◽  
Yoshihiro Gocho ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Luciferase Assay ◽  
Susceptibility Loci ◽  
Genome Wide ◽  
A Genome

Abstract Background Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts. Methods We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided. Results A novel risk locus in the USP7 gene (rs74010351, odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.27 to 1.65, P = 4.51 × 10–8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias. Conclusions These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).

scholarly journals Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia

2016 ◽  
Vol 34 (18) ◽  
pp. 2133-2140 ◽  
Author(s):  
Chengcheng Liu ◽  
Wenjian Yang ◽  
Meenakshi Devidas ◽  
Cheng Cheng ◽  
Deqing Pei ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Pancreatitis ◽  
Native American ◽  
Acute Lymphoblastic Leukemia ◽  
Genetic Risk ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Common Variants ◽  
Genome Wide

Purpose Acute pancreatitis is one of the common causes of asparaginase intolerance. The mechanism is unknown, and genetic predisposition to asparaginase-induced pancreatitis has not been previously identified. Methods To determine clinical risk factors for asparaginase-induced pancreatitis, we studied a cohort of 5,185 children and young adults with acute lymphoblastic leukemia, including 117 (2.3%) who were diagnosed with at least one episode of acute pancreatitis during therapy. A genome-wide association study was performed in the cohort and in an independent case-control group of 213 patients to identify genetic risk factors. Results Risk factors associated with pancreatitis included genetically defined Native American ancestry (P < .001), older age (P < .001), and higher cumulative dose of asparaginase (P < .001). No common variants reached genome-wide significance in the genome-wide association study, but a rare nonsense variant rs199695765 in CPA2, encoding carboxypeptidase A2, was highly associated with pancreatitis (hazard ratio, 587; 95% CI, 66.8 to 5166; P = 9.0 × 10−9). A gene-level analysis showed an excess of additional CPA2 variants in patients who did versus those who did not develop pancreatitis (P = .001). Sixteen CPA2 single-nucleotide polymorphisms were associated (P < .05) with pancreatitis, and 13 of 24 patients who carried at least one of these variants developed pancreatitis. Biologic functions that were overrepresented by common variants modestly associated with pancreatitis included purine metabolism and cytoskeleton regulation. Conclusion Older age, higher exposure to asparaginase, and higher Native American ancestry were independent risk factors for pancreatitis in patients with acute lymphoblastic leukemia. Those who inherit a nonsense rare variant in the CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis.

scholarly journals Screening Low-Frequency SNPS From Genome-Wide Association Study Reveals a New Risk Allele for Progression to AIDS

2011 ◽  
Vol 56 (3) ◽  
pp. 279-284 ◽  
Author(s):  
Sigrid Le Clerc ◽  
Cédric Coulonges ◽  
Olivier Delaneau ◽  
Danielle Van Manen ◽  
Joshua T Herbeck ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Low Frequency ◽  
Genome Wide Association ◽  
Genome Wide

908. Genome-Wide Association Study Identifies HTR2B as a Risk Variant of Cannabis-Related Aggression in African Americans

2017 ◽  
Vol 81 (10) ◽  
pp. S367
Author(s):  
Janitza Montalvo-Ortiz ◽  
Hang Zhou ◽  
Lindsay Farrer ◽  
Henry Kranzler ◽  
Joel Gelernter
Keyword(s):  
African Americans ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Risk Variant ◽  
Genome Wide

scholarly journals Genome wide association study of HTLV-1–associated myelopathy/tropical spastic paraparesis in the Japanese population

2021 ◽  
Vol 118 (11) ◽  
pp. e2004199118
Author(s):  
Marina Penova ◽  
Shuji Kawaguchi ◽  
Jun-ichirou Yasunaga ◽  
Takahisa Kawaguchi ◽  
Tomoo Sato ◽  
...  
Keyword(s):  
Amino Acid ◽  
Association Study ◽  
Proviral Load ◽  
Odds Ratio ◽  
Japanese Population ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

HTLV-1–associated myelopathy (HAM/TSP) is a chronic and progressive inflammatory disease of the central nervous system. The aim of our study was to identify genetic determinants related to the onset of HAM/TSP in the Japanese population. We conducted a genome-wide association study comprising 753 HAM/TSP patients and 899 asymptomatic HTLV-1 carriers. We also performed comprehensive genotyping of HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1 genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in HLA class I (P = 1.54 × 10−9) and class II (P = 1.21 × 10−8) loci with HAM/TSP. Association analysis using HLA genotyping results showed that HLA-C*07:02 (P = 2.61 × 10−5), HLA-B*07:02 (P = 4.97 × 10−10), HLA-DRB1*01:01 (P = 1.15 × 10−9) and HLA-DQB1*05:01 (P = 2.30 × 10−9) were associated with disease risk, while HLA-B*40:06 (P = 3.03 × 10−5), HLA-DRB1*15:01 (P = 1.06 × 10−5) and HLA-DQB1*06:02 (P = 1.78 × 10−6) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP (P = 9.52 × 10−10); individuals homozygous for leucine had an associated increased risk of HAM/TSP (odds ratio, 9.57), and proline was protective (odds ratio, 0.65). Both associations were independent of the known risk associated with proviral load. DRB1-GB-7-Leu was not significantly associated with proviral load. We have identified DRB1-GB-7-Leu as a genetic risk factor for HAM/TSP development independent of proviral load. This suggests that the amino acid residue may serve as a specific marker to identify the risk of HAM/TSP even without knowledge of proviral load. In light of its allele frequency worldwide, this biomarker will likely prove useful in HTLV-1 endemic areas across the globe.

scholarly journals Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Gut ◽  
2019 ◽  
Vol 68 (5) ◽  
pp. 854-865 ◽  
Author(s):  
Clemens Schafmayer ◽  
James William Harrison ◽  
Stephan Buch ◽  
Christina Lange ◽  
Matthias C Reichert ◽  
...  
Keyword(s):  
Diverticular Disease ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Population Based ◽  
Genome Wide Association ◽  
P Value ◽  
Risk Variant ◽  
Complex Disorder ◽  
Genome Wide ◽  
Epithelial Dysfunction

ObjectiveDiverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.DesignDiscovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.ResultsWe discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10−10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).ConclusionIn silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

Genome-Wide Association Study Identifies PNPLA3 I148M Variant Associated with Elevated Transaminase Levels after Induction Therapy in Pediatric ALL Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3714-3714 ◽  
Author(s):  
Christian A. Fernandez ◽  
Colton Smith ◽  
Wenjian Yang ◽  
Chengcheng Liu ◽  
Laura B. Ramsey ◽  
...  
Keyword(s):  
Association Study ◽  
Induction Therapy ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
African Ancestry ◽  
Alanine Transaminase ◽  
Genome Wide Association ◽  
Remission Induction ◽  
E Coli ◽  
Genome Wide

Abstract Current regimens for remission induction therapy of pediatric acute lymphoblastic leukemia (ALL) include multiple potentially hepatotoxic drugs, including asparaginase. The objective of our genome-wide association study (GWAS) was to identify genetic loci associated with elevated alanine transaminase (ALT) levels immediately after remission induction in children with ALL. The patients included were enrolled on St. Jude Children's Research Hospital (SJCRH) protocols Total XV (n = 373) or Total XVI (n = 342); germline DNA was genotyped using the Affymetrix 500K, Affymetrix 6.0, or the Illumina Exome Beadchip arrays. In multivariate analysis, risk factors associated with higher ALT included older age, higher body mass index, European (versus African) ancestry, treatment with PEGylated E. coli asparaginase (versus native E. coli asparaginase), and receiving additional doses of asparaginase during induction due to high level of minimal residual disease at day 15-19 of induction. GWAS identified an association between I148M PNPLA3 rs738409 (C>G) variant and post-induction ALT (Figure 1A; P = 7.9x10-9; median ALT of 34, 45, and 58 IU/L in CC, GC and GG genotypes, respectively), and the effect of the PNPLA3 variant was consistent for both protocols, both ALL risk groups, and among patients of European, African, and Hispanic ancestry. The PNPLA3 variant has previously been linked to elevated ALT and to the development of steatosis in adults;[PMID: 22001757; 18820647] in mice, this same variant led to a loss of catalytic function and to an increase of PNPLA3 accumulation in hepatic lipid droplets and to the development of steatosis.[PMID: 24917523] Within patients of African ancestry, we identified a variant near PIGV rs12748152 (C>T) associated with lower ALT levels at P = 1.7x10-8; median ALT of 28 and 6 IU/L in CC and TC genotypes, respectively (Figure 1B), consistent with lower ALT values observed in patients of African ancestry. The PIGV variant explained 7% of the variation in ALT for patients of African ancestry. The results of our study suggest that post-remission induction ALT levels may be related to treatment-related variables, such as increased asparaginase exposure, and to host genetic factors, at least some of which contribute to hepatic dysfunction in settings outside of ALL therapy. Figure 1. Alanine transaminase (ALT) levels by PNPLA3 or PIGV genotype Figure 1. Alanine transaminase (ALT) levels by PNPLA3 or PIGV genotype Disclosures Evans: Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.

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